Abstract 3432: Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics

Abstract

Abstract The p53 transcription factor functions as one of cancer's most potent tumor suppressors and is the most frequently mutated gene in human cancer. Restoration of wild type structure and function (so-called reactivation) of the high levels of the deficient mutant p53 protein with a small molecule is a highly sought after goal in anti-cancer drug development. We discovered a new class of small molecule zinc chelators named zinc metallochaperones (ZMCs) that reactivate zinc deficient mutant p53 through a novel mechanism by refolding p53 protein and inducing a p53 mediated apoptotic program. We identified the role of cellular zinc homeostasis as the OFF switch in ZMC pharmacodynamics indicating that a brief period of p53 mutant reactivation is sufficient for on-target efficacy. We conducted pre-clinical pharmacokinetic (PK), pharmacodymanic (PD) and efficacy studies in the murine pancreatic cancer (KPC) and BRCA1-deficient breast cancer models and found that ZMC1 and its new formulation of the drug in complex with zinc improved survival and inhibited tumor growth specifically for the zinc deficient allele. Using the BRCA1-deficient breast cancer model, we observed a highly synergistic effect of ZMC1 and the PARP inhibitor olaparib. Olaparib is now approved for the treatment of advanced BRCA1/2 mutant ovarian cancers, and recent clinical data also support its efficacy in BRCA1/2 mutant breast cancers. However acquired resistance to PARP inhibitors is inevitable in most advanced cancers. We investigated the ZMC therapeutic efficacy and found that the cell lines derived from olaparib resistant tumors are still sensitive to ZMC1 treatment. We are currently investigating the mechanism and testing the combination in vivo. In addition, we explored synergistic combinations of ZMC1 and other chemotherapy drugs based on its mechanism of action including ZMC1 with MDM2 antagonists and BCL2 antagonists. Overall, our findings indicate that the mutant p53 reactivational activity of ZMCs is governed by a unique ON/OFF switch mechanism that allows the compounds to be effective with a brief exposure to avoid the off target toxicities. The targeted and synergistic combinatorial treatments represent a significant departure from the traditional paradigm for developing a targeted molecular therapeutic in cancer. Citation Format: Xin Yu, Bing Na, Saif Zaman, Tracy Withers, John Gilleran, Alan J. Blayney, Anthony F. Bencivenga, Adam R. Blanden, Yue Liu, David A. Boothman, Stewart N. Loh, S. David Kimball, Shridar Ganesan, Darren R. Carpizo. Zinc metallochaperones for mutant p53 reactivation in cancer therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3432.